Circulating vitamin D concentrations and the risk of urticaria: A bidirectional two-sample Mendelian randomization study.

Background and objectives: Vitamin D deficiency has been linked to urticaria, but causality remains uncer-tain. We used Mendelian randomization (MR) to investigate potential causal effects of vitamin D and its me-tabolites on urticaria risk.

Methods and study design: Summary statistics from genome-wide association studies (GWAS) of total 25-hydroxyvitamin D [25(OH)D] (n=120,618), 25-hydroxyvitamin D3 [25(OH)D3] (n=40,562), and C3-epimer-25-hydroxyvitamin D3 [C3-epi-25(OH)D3] (n=40,562) in Europeans were used, along with data on urticaria and its subtypes from FinnGen consortium (R10 release). For validation, we performed additional MR analyses using a larger dataset that meta-analyzed data from the UK Biobank and GWAS results from the SUNLIGHT consortium (n=496,946) as exposure variables. We performed compre-hensive sensitivity analyses, including heterogeneity tests, pleiotropy assessments, and leave-one-out analyses to evaluate result robustness. Statistical power calculations were conducted to validate the reliability of our findings.

Results: MR analysis revealed a causal protective effect of higher total 25(OH)D levels on urticaria risk [odds ratio (OR) = 0.81, 95% confidence interval (CI):0.69-0.95, p =0.008, statistical power = 81.1%]. Similar causal effects were observed for 25(OH)D3 levels (OR = 0.85, 95% CI: 0.74-0.98, p = 0.023, statistical power = 67.4%).These findings were validated in the replication cohort using serum 25(OH)D measurements (OR = 0.69, 95%CI: 0.56-0.85, p = 0.001, statistical power = 96.1%). Sensitivity analyses showed no significant heterogeneity or pleiotropy. Reverse MR analysis found no evidence that genetic risk of urticaria affects vitamin D levels, suggesting a potentially unidirectional causal relationship.

Conclusions: This study provides the first genetic evidence that higher vitamin D levels may reduce urticaria risk, offering a new theoretical basis for urticaria prevention and treatment strategies.